Data from Phase III trials of the AZD1222 coronavirus vaccine being co-developed by AstraZeneca and the University of Oxford were published in The Lancet on Tuesday, reaffirming the candidate's safety profile and providing some additional evidence that halving the first dose of the two-dose regimen boosts its effectiveness. The true efficacy of AZD1222 has been dogged by uncertainty since an interim analysis showed it was between 62% and 90% effective, but that the higher results were observed in a small subset of volunteers who had mistakenly been given a lower initial dose.
However, CEO Pascal Soriot said the peer-reviewed publication provides "full disclosure of the Oxford programme interim analysis," with the data showing AZD1222 "is effective against COVID-19, with in particular no severe infections and no hospitalisations in the vaccine group, as well as [being] safe and well tolerated." He added "we have begun submitting data to regulatory authorities around the world for early approval and our global supply chains are up and running, ready to quickly begin delivering hundreds of millions of doses on a global scale at no profit."
Last month, AstraZeneca reported a combined interim analysis based on pooled data from the COV002 Phase II/III trial in the UK and the COV003 Phase III study in Brazil. It said volunteers who had received the correct regimen, consisting of two standard doses of AZD1222 given at least a month apart (SD/SD cohort), saw around 62% protection. However, a subset in the UK trial who had received a half dose as their first jab, and then a standard dose as their second (LD/SD cohort), appeared to have 90% protection against symptomatic COVID-19. Combining the two gave the average of around 70%. Moreover, there were fewer participants in this LD/SD cohort, and all of them were also under 55 years old, while the full-dose group included people ages 56 to 69 as well as those 70 years and up, raising questions about whether the lower dosing would also be effective in older populations. Soriot later said AstraZeneca would conduct an additional study that would test an initial low-dose of the vaccine.
The analysis published in The Lancet on Tuesday included data from 11,636 participants in COV002 and COV003. The analysis also looked at two other smaller Phase I/II studies, dubbed COV001 and COV005, conducted in the UK and South Africa, respectively. Participants had been randomised to receive AZD1222 or comparator, consisting of meningococcal vaccine MenACWY. The findings confirmed that among the 4440 SD/SD recipients, vaccine efficacy was 62.1%, with 27 cases of COVID-19 recorded in this group. Efficacy rose to 90% among the 1367 LD/SD recipients, where there were three cases of COVID-19. Overall vaccine efficacy across both groups was 70.4%, with 30 cases of COVID-19 occurring in all 5807 vaccinated volunteers, versus 101 cases in the comparator group, for a total of 131 in the studies.
Results also showed that more than 21 days after the first dose, there were 10 cases hospitalised for COVID-19, all in the control arm. Two of the cases were assessed as having severe COVID-19, including one death. In addition, five cases occurred in participants older than 55 years of age, although "vaccine efficacy in older age groups could not be assessed, but will be determined, if sufficient data are available, in a future analysis after more cases have accrued," the study authors said. However, co-author Andrew Pollard, director of the Oxford Vaccine Group, suggested that "the evidence we have so far on the immune response very much suggests that it's likely to be similar levels of protection across the ages."
Meanwhile, The Lancet report said asymptomatic infections or those with unreported symptoms were detected in 69 participants enrolled in COV002, with 29 instances among vaccinated participants and 40 for controls, for a vaccine efficacy rate of 27.3%. Of the 29 recorded in the vaccine group, 22 cases occurred among SD/SD recipients and seven were in LD/SD recipients, which the authors said works out to vaccine efficacy of 3.8% and 58.9%, respectively. There was no testing plan for asymptomatic infections in the Brazil COV003 study.
The authors noted that in participants who received two standard doses, "efficacy against primary symptomatic COVID-19 was consistent in both the UK and Brazil [studies], indicating these results are generalisable across two diverse settings with different timings for the booster dose." However, they called the efficacy seen in those who received a low dose as prime in the UK "intriguingly high" compared with other findings in the trial. "Although there is a possibility that chance might play a part in such divergent results, a similar contrast in efficacy between the LD/SD and SD/SD recipients with asymptomatic infections provides support for the observation," the researchers said.
The study authors noted that AZD1222 had a "good safety profile with serious adverse events and adverse events of special interest balanced across the study arms." At the interim analysis, participants were followed for a median of 3.4 months, during which time 175 severe adverse events occurred in 168 participants, including 84 events in the AZD1222 group and 91 among controls. The overall reported rates of serious adverse events were 0.7% in the vaccine group and 0.8% in the control group. The study authors said three events were considered "possibly related to either the experimental or a control vaccine."
A case of transverse myelitis was reported 14 days after AZD1222 booster vaccination as being possibly related to the vaccine candidate. The case led to AZD1222 studies being temporarily halted in September, although they fully resumed by around late October. The study authors noted that an independent neurological committee considered "the most likely diagnosis to be of an idiopathic, short segment, spinal cord demyelination." They also said there were two additional cases of transverse myelitis that were originally reported as potentially linked to vaccination, "but later determined [as] unlikely to be related" by an independent committee of neurological experts. One instance that occurred 10 days after a first dose of AZD1222 turned out to be a case of pre-existing, but previously unrecognised multiple sclerosis, while the second case was reported 68 days after MenACWY vaccination.
Bloomberg Intelligence analyst Sam Fazeli remarked that while the efficacy rate may be enough to get AZD1222 approved, the variability in different subgroups and lack of data for older people should give regulators pause in rushing this through. "I would wait until at least the US trial [of AZD1222] – which is much more tightly controlled in terms of dosing and intervals between doses – reads out before approving the vaccine," he added. Vaccines developed by Pfizer/BioNTech and Moderna have both shown efficacies above 90%.
Meanwhile, Mene Pangalos, head of BioPharmaceuticals R&D at AstraZeneca, said he hoped requests for approval from regulators around the globe could still be submitted this year. "We hope that once the regulatory authorities review the data, we can get approval any time from the completion of the submission, which could be any time from the end of this year to early next year," he added.
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